Chapter 5 : Pneumolysin and Other Virulence Proteins

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(the pneumococcus) makes a range of molecules that can be considered virulence factors. The organism also makes a range of protein virulence factors, including surface proteins (choline-binding proteins, LPXTG-anchored proteins, and lipoproteins) as well as a range of enzymes (superoxide dismutase, NADH oxidase, zinc metalloproteinases) and the pore-forming toxin pneumolysin (PLY). This chapter focuses on PLY and some of the other protein virulence factors of the pneumococcus. The toxin can have other effects on cells and has been shown to affect the production of proinflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and IL-6. It was shown that PLY contributes to neuronal damage in a rabbit model of pneumococcal meningitis. An effect of PLY on calcium levels has also been demonstrated in neuroblastoma cells, in which purified PLY was shown to induce apoptosis in a calcium-dependent manner. The changes in calcium levels were due to pore formation by the toxin rather than opening of voltage-gated Ca channels. This study also showed that mitogen-activated protein kinase p38 was important in PLY-induced cell death. The overall virulence gene content of the pneumococcus will presumably dictate its ability to cause disease.

Citation: Mitchell T. 2004. Pneumolysin and Other Virulence Proteins, p 61-74. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch5
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1. Alcantara, R. B.,, L. C. Preheim,, and M. J. Gentry-Nielsen. 2001. Pneumolysin-induced complement depletion during experimental pneumococcal bacteremia. Infect. Immun. 69: 3569 3575.
2. Alexander, J. E.,, A. M. Berry,, J. C. Paton,, J. B. Rubins,, P. W. Andrew,, and T. J. Mitchell. 1998. The course of pneumococcal pneumonia is altered by amino acid changes affecting the activity of pneumolysin. Microb. Pathog. 24: 167 174.
3. Alfzelius, B. A. 1979. The immotile-cilia syndrome and other ciliary diseases. Int. Rev. Exp. Pathol. 19: 1 43.
4. Amee, F. Z.,, S. D. Comis,, and M. P. Osbourne. 1995. N G-methyl-L-arginine protects the guinea pig cochlea from the cytotoxic effects of pneumolysin. Acta Oto-Laryngol. 115: 386 391.
5. Auzat, I.,, S. Chapuy-Regaud,, G. Le Bras,, D. Dos Santos,, A. D. Ogunniyi,, I. Le Thomas,, J.-R. Garel,, J. C. Paton,, and M.-C. Trombe. 1999. The NADH oxidase of Streptococcus pneumoniae: its involvement in competence and virulence. Mol. Microbiol. 34: 1018 1028.
6. Baba, H.,, I. Kawamura,, C. Kohda,, T. Nomura,, Y. Ito,, T. Kimoto,, I. Watanabe,, S. Ichiyama,, and M. Mitsuyama. 2001. Essential role of domain 4 of pneumolysin from Streptococcus pneumoniae in cytolytic activity as determined by truncated proteins. Biochem. Biophys. Res. Commun. 281: 37 44.
7. Badwey, J. A.,, J. T. Curnutte,, J. M. Robinson,, C. B. Berde,, M. J. Karnovsky,, and M. L. Karnovsky. 1984. Effects of free fatty acids on release of superoxide and on change of shape by human neutrophils. Reversibility by albumin. J. Biol. Chem. 259: 7870 7877.
8. Balachandran, P.,, S. K. Hollingshead,, J. C. Paton,, and D. E. Briles. 2001. The autolytic enzyme LytA of Streptococcus pneumoniae is not responsible for releasing pneumolysin. J. Bacteriol. 183: 3108 3116.
9. Benton, K.,, M. Everson,, and D. Briles. 1995. A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice. Infect. Immun. 63: 448 455.
10. Benton, K.,, J. Paton,, and D. Briles. 1997. Differences in virulence for mice among Streptococcus pneumoniae strains of capsular types 2, 3, 4, 5, and 6 are not attributable to differences in pneumolysin production. Infect. Immun. 65: 1237 1244.
11. Benton, K. A.,, J. C. Paton,, and D. E. Briles. 1997. The hemolytic and complement-activating properties of pneumolysin do not contribute individually to virulence in a pneumococcal bacteremia model. Microb. Pathog. 23: 201 209.
12. Benton, K. A.,, J. L. VanCott,, and D. E. Briles. 1998. Role of tumor necrosis factor alpha in the host response of mice to bacteremia caused by pneumolysin-deficient Streptococcus pneumoniae. Infect. Immun. 66: 839 842.
13. Berry, A.,, J. Alexander,, T. Mitchell,, P. Andrew,, D. Hansman,, and J. Paton. 1995. Effect of defined point mutations in the pneumolysin gene on the virulence of Streptococcus pneumoniae. Infect. Immun. 63: 1969 1974.
14. Berry, A. M.,, R. A. Lock,, D. Hansman,, and J. C. Paton. 1989. Contribution of autolysin to virulence of Streptococcus pneumoniae. Infect. Immun. 57: 2324 2330.
15. Berry, A. M.,, A. D. Ogunniyi,, D. C. Miller,, and J. C. Paton. 1999. Comparative virulence of Streptococcus pneumoniae strains with insertion-duplication, point, and deletion mutations in the pneumolysin gene. Infect. Immun. 67: 981 985.
16. Berry, A. M.,, and J. C. Paton. 2000. Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins. Infect. Immun. 68: 133 140.
17. Berry, A. M.,, and J. C. Paton. 1996. Sequence heterogeneity of PsaA, a 37-kilodalton putative adhesin essential for virulence of Streptococcus pneumoniae. Infect. Immun. 64: 5255 5262.
18. Berry, A. M.,, J. Yother,, D. E. Briles,, D. Hansman,, and J. C. Paton. 1989. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect. Immun. 57: 2037 2042.
19. Bethe, G.,, R. Nau,, A. Wellmer,, R. Hakenbeck,, R. R. Reinert,, H.-P. Heinz,, and G. Zysk. 2001. The cell wall-associated serine protease PrtA: a highly conserved virulence factor of Streptococcus pneumoniae. FEMS Microbiol. Lett. 205: 99 103.
20. Blue, C. E.,, G. K. Paterson,, A. R. Kerr,, M. Berge,, J. P. Claverys,, and T. J. Mitchell. 2003. ZmpB, a novel virulence factor of Streptococcus pneumoniae that induces tumor necrosis factor alpha production in the respiratory tract. Infect. Immun. 71: 4925 4935.
21. Boulnois, G. J.,, J. C. Paton,, T. J. Mitchell,, and P. W. Andrew. 1991. Structure and function of pneumolysin, the multifunctional, thiol-activated toxin of Streptococcus pneumoniae. Mol. Microbiol. 5: 2611 2616.
22. Braun, J. S.,, R. Novak,, G. Gao,, P. J. Murray,, and J. L. Shenep. 1999. Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages. Infect. Immun. 67: 3750 3756.
23. Braun, J. S.,, J. E. Sublett,, D. Freyer,, T. J. Mitchell,, J. L. Cleveland,, E. I. Tuomanen,, and J. R. Weber. 2002. Pneumococcal pneumolysin and H 2O2 mediate brain cell apoptosis during meningitis. J. Clin. Investig. 109: 19 27.
24. Cabellos, C.,, D. E. MacIntyre,, M. Forrest,, M. Burroughs,, S. Prasad,, and E. Tuomanen. 1992. Differing roles for platelet-activating factor during inflammation of the lung and sub-arachnoid space: the special case of Streptococcus pneumoniae. J. Clin. Investig. 90: 612 618.
25. Camara, M.,, G. J. Boulnois,, P. W. Andrew,, and T. J. Mitchell. 1994. A neuraminidase from Streptococcus pneumoniae has the features of a surface protein. Infect. Immun. 62: 3688 3695.
26. Canvin, J. R.,, A. P. Marvin,, M. Sivakumaran,, J. C. Paton,, G. J. Boulnois,, P. W. Andrew,, and T. J. Mitchell. 1995. The role of pneumolysin and autolysin in the pathology of pneumonia and septicemia in mice infected with a type-2 pneumococcus. J. Infect. Dis. 172: 119 123.
27. Chiavolini, D.,, G. Memmi,, T. Maggi,, F. Iannelli,, G. Pozzi,, and M. Oggioni. 2003. The three extra-cellular zinc metalloproteinases of Streptococcus pneumoniae have a different impact on virulence in mice. BMC Microbiol. 3: 14.
28. Cockeran, R.,, C. Durandt,, C. Feldman,, T. J. Mitchell,, and R. Anderson. 2002. Pneumolysin activates the synthesis and release of interleukin- 8 by human neutrophils in vitro. J. Infect. Dis. 186: 562 565.
29. Cockeran, R.,, H. C. Steel,, T. J. Mitchell,, C. Feldman,, and R. Anderson. 2001. Pneumolysin potentiates production of prostaglandin E 2 and leukotriene B 4 by human neutrophils. Infect. Immun. 69: 3494 3496.
30. Cockeran, R.,, A. J. Theron,, H. C. Steel,, N. M. Matlola,, T. J. Mitchell,, C. Feldman,, and R. Anderson. 2001. Proinflammatory interactions of pneumolysin with human neutrophils. J. Infect. Dis. 183: 604 611.
31. Comis, S. D.,, M. P. Osborne,, J. Stephen,, M. J. Tarlow,, T. L. Hayward,, T. J. Mitchell,, P. A. Andrew,, and G. J. Boulnois. 1993. Cytotoxic effect on hair cells of the guinea pig cochlea produced by pneumolysin, the thiol activated toxin of Streptococcus pneumoniae. Acta Oto-Laryngol. 113: 152 159.
32. Cundell, D. R.,, B. J. Pearce,, J. Sandros,, A. M. Naughton,, and H. R. Masure. 1995. Peptide permeases from Streptococcus pneumoniae affect adherence to eucaryotic cells. Infect. Immun. 63: 2493 2498.
33. Curnutte, J. T.,, J. M. Badwey,, J. M. Robinson,, M. J. Karnovsky,, and M. L. Karnovsky. 1984. Studies on the mechanism of superoxide release from human neutrophils stimulated with arachidonate. J. Biol. Chem. 259: 11851 11857.
34. Dintilhac, A.,, G. Alloing,, C. Granadel,, and J. P. Claverys. 1997. Competence and virulence of Streptococcus pneumoniae: Adc and PsaA mutants exhibit a requirement for Zn and Mn resulting from inactivation of putative ABC metal permeases. Mol. Microbiol. 25: 727 739.
35. Dockrell, D. H.,, M. Lee,, D. H. Lynch,, and R. C. Read. 2001. Immune-mediated phagocytosis and killing of Streptococcus pneumoniae are associated with direct and bystander macrophage apoptosis. J. Infect. Dis. 184: 713 722.
36. Duane, P. G.,, J. B. Rubins,, H. R. Weisel,, and E. N. Janoff. 1993. Identification of hydrogen peroxide as a Streptococcus pneumoniae toxin for rat alveolar epithelial cells. Infect. Immun. 61: 4392 4397.
37. Engel, F.,, R. Blatz,, J. Kellner,, M. Palmer,, U. Weller,, and S. Bhakdi. 1995. Breakdown of the round window permeability barrier evoked by streptolysin O: possible etiologic role in development of sensorineural hearing loss in acute otitis media. Infect. Immun. 63: 1305 1310.
38. Feldman, C.,, R. Anderson,, R. Cockeran,, T. Mitchell,, P. Cole,, and R. Wilson. 2002. The effects of pneumolysin and hydrogen peroxide, alone and in combination, on human ciliated epithelium in vitro. Respir. Med. 96: 580 585.
39. Feldman, C.,, T. J. Mitchell,, P. W. Andrew,, G. J. Boulnois,, R. C. Read,, H. C. Todd,, P. J. Cole,, and R. Wilson. 1990. The effect of Streptococcus pneumoniae pneumolysin on human respiratory epithelium in vitro. Microb. Pathog. 9: 275 284.
40. Feldman, C.,, N. C. Munro,, P. K. Jeffery,, T. J. Mitchell,, P. W. Andrew,, G. J. Boulnois,, D. Guerreiro,, J. A. L. Rohde,, H. C. Todd,, P. J. Cole,, and R. Wilson. 1991. Pneumolysin induces the salient histologic features of pneumococcal infection in the rat lung in vivo. Am. J. Respir. Cell Mol. Biol. 5: 416 423.
41. Fitzgerald, T. J.,, and L. A. Repesh. 1987. The hyaluronidase associated with Treponema pallidum facilitates treponemal dissemination. Infect. Immun. 55: 1023 1028.
42. Fortnum, H. M. 1992. Hearing impairment after bacterial meningitis: a review. Arch. Dis. Child. 67: 1128 1133.
43. Friedland, I. R.,, M. M. Paris,, S. Hickey,, S. Shelton,, K. Olsen,, J. C. Paton,, and G. H. McCracken. 1995. The limited role of pneumolysin in the pathogenesis of pneumococcal meningitis. J. Infect. Dis. 172: 805 809.
44. Harrison, J. C.,, Z. A. Karcioglu,, and M. K. Johnson. 1982-1983. Response of leukopenic rabbits to pneumococcal toxin. Curr. Eye Res. 2: 705 710.
45. Hava, D.,, and A. Camilli. 2002. Large-scale identification of serotype 4 Streptococcus pneumoniae virulence factors. Mol. Microbiol. 45: 1389 1406.
46. Hirst, R. A.,, A. Rutman,, K. Sikand,, P. W. Andrew,, T. J. Mitchell,, and C. Ocallaghan. 2000. Effect of pneumolysin on rat brain ciliary function: comparison of brain slices with cultured ependymal cells. Pediatr. Res. 47: 381 384.
47. Hirst, R. A.,, K. S. Sikand,, A. Rutman,, T. J. Mitchell,, P. W. Andrew,, and C. Ocallaghan. 2000. Relative roles of pneumolysin and hydrogen peroxide from Streptococcus pneumoniae in inhibition of ependymal ciliary beat frequency. Infect. Immun. 68: 1557 1562.
48. Holtzman, M. J. 1991. Arachidonic acid metabolism. Implications of biological chemistry for lung function and disease. Am. Rev. Respir. Dis. 143: 188 203.
49. Humphrey, J. H. 1948. Hyaluronidase production by pneumococci. J. Pathol. Bacteriol. 55: 273 275.
50. Irwin, C. R.,, S. L. Schor,, and M. W. Ferguson. 1994. Effects of cytokines on gingival fibroblasts in vitro are modulated by the extracellular matrix. J. Periodontal Res. 29: 309 317.
51. Johnson, M. K.,, and J. H. Allen. 1975. The role of cytolysin in pneumococcal ocular infection. Am. J. Ophthalmol. 80: 518 520.
52. Johnson, M. K.,, J. A. Hobden,, M. Hagenah,, R. J. OCallaghan,, J. M. Hill,, and S. Chen. 1990. The role of pneumolysin in ocular infections with Streptococcus pneumoniae. Curr. Eye Res. 9: 1107 1114.
53. Jounblat, R.,, A. Kadioglu,, T. J. Mitchell,, and P. W. Andrew. 2003. Pneumococcal behavior and host responses during bronchopneumonia are affected differently by the cytolytic and complement-activating activities of pneumolysin. Infect. Immun. 71: 1813 1819.
54. Kadioglu, A.,, N. A. Gingles,, K. Grattan,, A. Kerr,, T. J. Mitchell,, and P. W. Andrew. 2000. Host cellular immune response to pneumococcal lung infection in mice. Infect. Immun. 68: 492 501.
55. Kadioglu, A.,, S. Taylor,, F. Iannelli,, G. Pozzi,, T. J. Mitchell,, and P. W. Andrew. 2002. Upper and lower respiratory tract infection by Streptococcus pneumoniae is affected by pneumolysin deficiency and differences in capsule type. Infect. Immun. 70: 2886 2890.
56. Kerr, A. R.,, J. J. Irvine,, J. J. Search,, N. A. Gingles,, A. Kadioglu,, P. W. Andrew,, W. L. McPheat,, C. G. Booth,, and T. J. Mitchell. 2002. Role of inflammatory mediators in resistance and susceptibility to pneumococcal infection. Infect. Immun. 70: 1547 1557.
57. Kharat, A. S.,, and A. Tomasz. 2003. Inactivation of the srtA gene affects localization of surface proteins and decreases adhesion of Streptococcus pneumoniae to human pharyngeal cells in vitro. Infect. Immun. 71: 2758 2765.
58. Korchev, Y. E.,, C. L. Bashford,, C. Pederzolli,, C. A. Pasternak,, P. J. Morgan,, P. W. Andrew,, and T. J. Mitchell. 1998. A conserved tryptophan in pneumolysin is a determinant of the characteristics of channels formed by pneumolysin in cells and planar lipid bilayers. Biochem. J. 329: 571 577.
59. Kostyukova, N. N.,, M. O. Volkova,, V. V. Ivanova,, and A. S. Kvetnaya. 1995. A study of pathogenic factors of Streptococcus pneumoniae strains causing meningitis. FEMS Immunol. Med. Microbiol. 10: 133 137.
60. Linder, T. E.,, R. L. Daniels,, D. J. Lim,, and T. F. DeMaria. 1994. Effect of intranasal inoculation of Streptococcus pneumoniae on the structure of the surface carbohydrates of the chinchilla eustachian tube and middle ear mucosa. Microb. Pathog. 16: 435 441.
61. Malley, R.,, P. Henneke,, S. C. Morse,, M. J. Cieslewicz,, M. Lipsitch,, C. M. Thompson,, E. Kurt-Jones,, J. C. Paton,, M. R. Wessels,, and D. T. Golenbock. 2003. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl. Acad. Sci. USA 100: 1966 1971.
62. Marra, A.,, S. Lawson,, J. S. Asundi,, D. Brigham,, and A. E. Hromockyj. 2002. In vivo characterization of the psa genes from Streptococcus pneumoniae in multiple models of infection. Microbiology 148: 1483 1491.
63. McKee, C. M.,, M. B. Penno,, M. Cowman,, M. D. Burdick,, R. M. Strieter,, C. Bao,, and P. W. Noble. 1996. Hyaluronan (HA) fragments induce chemokine gene-expression in alveolar macrophages—the role of HA size and CD44. J. Clin. Investig. 98: 2403 2413.
64. Mitchell, T. J.,, P. W. Andrew,, F. K. Saunders,, A. N. Smith,, and G. J. Boulnois. 1991. Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute-phase protein. Mol. Microbiol. 5: 1883 1888.
65. Mohammed, B. J.,, T. J. Mitchell,, P. W. Andrew,, R. A. Hirst,, and C. Ocallaghan. 1999. The effect of the pneumococcal toxin, pneumolysin on brain ependymal cilia. Microb. Pathog. 27: 303 309.
66. Morgan, P. J.,, S. C. Hyman,, A. J. Rowe,, T. J. Mitchell,, P. W. Andrew,, and H. R. Saibil. 1995. Subunit organisation and symmetry of pore-forming oligomeric pneumolysin. FEBS Lett. 371: 77 80.
67. Ng, E. W. M.,, N. Samiy,, J. B. Rubins,, F. V. Cousins,, K. L. Ruoff,, A. S. Baker,, and D. J. D’Amico. 1997. Implication of pneumolysin as a virulence factor in Streptococcus pneumoniae endophthalmitis. Retina 17: 521 529.
68. Oggioni, M. R.,, G. Memmi,, T. Maggi,, D. Chiavolini,, F. Iannelli,, and G. Pozzi. 2003. Pneumococcal zinc metalloproteinase ZmpC cleaves human matrix metalloproteinase 9 and is a virulence factor in experimental pneumonia. Mol. Microbiol. 49: 795 805.
69. Ogunniyi, A. D.,, R. L. Folland,, D. E. Briles,, S. K. Hollingshead,, and J. C. Paton. 2000. Immunization of mice with combinations of pneumococcal virulence proteins elicits enhanced protection against challenge with Streptococcus pneumoniae. Infect. Immun. 68: 3028 3033.
70. Paton, J. C.,, and A. Ferrante. 1983. Inhibition of human polymorphonuclear leukocyte respiratory burst, bactericidal activity, and migration by pneumolysin. Infect. Immun. 41: 1212 1216.
71. Paton, J. C.,, B. Rowan-Kelly,, and A. Ferrante. 1984. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 43: 1085 1087.
72. Pericone, C. D.,, K. Overweg,, P. W. M. Hermans,, and J. N. Weiser. 2000. Inhibitory and bactericidal effects of hydrogen peroxide production by Streptococcus pneumoniae on other inhabitants of the upper respiratory tract. Infect. Immun. 68: 3990 3997.
73. Rossjohn, J.,, S. C. Feil,, W. J. McKinstry,, R. K. Tweten,, and M. W. Parker. 1997. Structure of a cholesterol-binding, thiol-activated cytolysin and a model of its membrane form. Cell 89: 685 692.
74. Rossjohn, J.,, R. J. C. Gilbert,, D. Crane,, P. J. Morgan,, T. J. Mitchell,, A. J. Rowe,, P. W. Andrew,, J. C. Paton,, R. K. Tweten,, and M. W. Parker. 1998. The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae. J. Mol. Biol. 284: 449 461.
75. Rubins, J. B.,, D. Charboneau,, C. Fasching,, A. M. Berry,, J. C. Paton,, J. E. Alexander,, P. W. Andrew,, T. J. Mitchell,, and E. N. Janoff. 1996. Distinct role for pneumolysin’s cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia. Am. J. Respir. Crit. Care Med. 153: 1339 1346.
76. Rubins, J. B.,, P. G. Duane,, D. Clawson,, D. Charboneau,, J. Young,, and D. E. Niewoehner. 1993. Toxicity of pneumolysin to pulmonary alveolar epithelial cells. Infect. Immun. 61: 1352 1358.
77. Rubins, J. B.,, T. J. Mitchell,, P. W. Andrew,, and D. E. Niewoehner. 1994. Pneumolysin activates phospholipase A in pulmonary artery endothelial cells. Infect. Immun. 62: 3829 3836.
78. Rubins, J. B.,, A. H. Paddock,, D. Charboneau,, A. M. Berry,, J. C. Paton,, and E. N. Janoff. 1998. Pneumolysin in pneumococcal adherence and colonization. Microb. Pathog. 25: 337 342.
79. Sato, K.,, M. Quartey,, C. Liebeler,, C. Le,, and G. Giebink. 1996. Roles of autolysin and pneumolysin in middle ear inflammation caused by a type 3 Streptococcus pneumoniae strain in the chinchilla otitis media model. Infect. Immun. 64: 1140 1145.
80. Saunders, F. K.,, T. J. Mitchell,, J. A. Walker,, P. W. Andrew,, and G. J. Boulnois. 1989. Pneumolysin, the thiol-activated toxin of Streptococcus pneumoniae, does not require a thiol group for in vitro activity. Infect. Immun. 57: 2547 2552.
81. Spellerberg, B.,, D. R. Cundell,, J. Sandros,, B. J. Pearce,, I. Idanpaan-Heikkila,, C. Rosenow,, and H. R. Masure. 1996. Pyruvate oxidase, as a determinant of virulence in Streptococcus pneumoniae. Mol. Microbiol. 19: 803 813.
82. Spreer, A.,, H. Kerstan,, T. Bottcher,, J. Gerber,, A. Siemer,, G. Zysk,, T. J. Mitchell,, H. Eiffert,, and R. Nau. 2003. Reduced release of pneumolysin by Streptococcus pneumoniae in vitro and in vivo after treatment with nonbacteriolytic antibiotics in comparison to ceftriaxone. Antimicrob. Agents Chemother. 47: 2649 2654.
83. Stringaris, A. K.,, J. Geisenhainer,, F. Bergmann,, C. Balshusemann,, U. Lee,, G. Zysk,, T. J. Mitchell,, B. U. Keller,, U. Kuhnt,, and J. Gerber. 2002. Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase. Neurobiol. Dis. 11: 355 368.
84. Talkington, D. F.,, B. G. Brown,, J. A. Tharpe,, A. Koenig,, and H. Russell. 1996. Protection of mice against fatal pneumococcal challenge by immunization with pneumococcal surface adhesin A (PsaA). Microb. Pathog. 21: 17 22.
85. Tettelin, H.,, K. E. Nelson,, I. T. Paulsen,, J. A. Eisen,, T. D. Read,, S. Peterson,, J. Heidelberg,, R. T. DeBoy,, D. H. Haft,, R. J. Dodson,, A. S. Durkin,, M. Gwinn,, J. F. Kolonay,, W. C. Nelson,, J. D. Peterson,, L. A. Umayam,, O. White,, S. L. Salzberg,, M. R. Lewis,, D. Radune,, E. Holtzapple,, H. Khouri,, A. M. Wolf,, T. R. Utterback,, C. L. Hansen,, L. A. McDonald,, T. V. Feldblyum,, S. Angiuoli,, T. Dickinson,, E. K. Hickey,, I. E. Holt,, B. J. Loftus,, F. Yang,, H. O. Smith,, J. C. Venter,, B. A. Dougherty,, D. A. Morrison,, S. K. Hollingshead,, and C. M. Fraser. 2001. Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 293: 498 506.
86. Tong, H. H.,, L. E. Blue,, M. A. James,, and T. F. DeMaria. 2000. Evaluation of the virulence of a Streptococcus pneumoniae neuraminidase-deficient mutant in nasopharyngeal colonization and development of otitis media in the chinchilla model. Infect. Immun. 68: 921 924.
87. Watson, D. A.,, and D. M. Musher. 1990. Interuption of capsule production in Streptococcus pneumoniae type serotype 3 by insertion of Tn 916. Infect. Immun. 58: 3135 3138.
88. Wellmer, A.,, G. Zysk,, J. Gerber,, T. Kunst,, M. von Mering,, S. Bunkowski,, H. Eiffert,, and R. Nau. 2002. Decreased virulence of a pneumolysin-deficient strain of Streptococcus pneumoniae in murine meningitis. Infect. Immun. 70: 6504 6508.
89. Winter, A. J.,, S. D. Comis,, M. P. Osborne,, M. J. Tarlow,, J. Stephen,, P. W. Andrew,, J. Hill,, and T. J. Mitchell. 1997. A role for pneumolysin but not neuraminidase in the hearing loss and cochlear damage induced by experimental pneumococcal meningitis in guinea pigs. Infect. Immun. 65: 4411 4418.
90. Yesilkaya, H.,, A. Kadioglu,, N. Gingles,, J. E. Alexander,, T. J. Mitchell,, and P. W. Andrew. 2000. Role of manganese-containing superoxide dismutase in oxidative stress and virulence of Streptococcus pneumoniae. Infect. Immun. 68: 2819 2826.
91. Yoshimura, A.,, E. Lien,, R. R. Ingalls,, E. Tuomanen,, R. Dziarski,, and D. Golenbock. 1999. Cutting edge: recognition of gram-positive bacterial cell wall components by the innate immune system occurs via toll-like receptor 2. J. Immunol. 163: 1 5.
92. Zwijnenburg, P. J. G.,, T. van der Poll,, S. Florquin,, S. Akira,, K. Takeda,, J. J. Roord,, and A. M. van Furth. 2003. Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis. J. Neuroimmunol. 138: 31 37.
93. Zysk, G.,, L. Bejo,, B. K. Schneider-Wald,, R. Nau,, and H.-P. Heinz. 2000. Induction of necrosis and apoptosis of neutrophil granulocytes by Streptococcus pneumoniae. Clin. Exp. Immunol. 122: 61 66.
94. Zysk, G.,, B. K. Schneider-Wald,, J. H. Hwang,, L. Bejo,, K. S. Kim,, T. J. Mitchell,, R. Hakenbeck,, and H.-P. Heinz. 2001. Pneumolysin is the main inducer of cytotoxicity to brain microvascular endothelial cells caused by Streptococcus pneumoniae. Infect. Immun. 69: 845 852.

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